Cell fate specification and tissue growth are fundamental to 0rganogenesis. Secreted signaling molecules of the TGFbeta and other families are key regulators of pattern formation and growth in many organs. However, the effector proteins through which these signaling pathways induce organ growth and the mechanisms that determine organ size are largely unknown. Our long-term goal is to elucidate the molecular pathways that control organ growth and signal cells to stop proliferating when an organ has attained its proper size. We are using the Drosophila eye as a genetic model system to study genes that control organ growth. In the proposed research, we focus on two previously uncharacterized genes, king kong (kik) and hippo, that we identified by mutagenesis screening. Mutations in kik and hippo have the same apparent phenotypes and produce proportionally enlarged organs containing more cells, kik and hippo specifically regulate cell proliferation but do not effect cell size or pattern formation. In contrast, manipulations of the known cell cycle and cell growth regulators effect cell size in addition to cell number. Thus, kik and hippo may reveal a novel pathway that specifically regulates organ growth. Our Specific Aims are (1) to quantitate the effects of kik and hippo on cell cycle progression and cell growth, (2) to determine whether Kik and Hippo mediate the growth-inducing activities of morphogen signaling molecules by testing for interaction between kik/hippo and signaling by the Drosophila TGFbeta homolog Decapentaplegic, (3) to characterize the kik and hippo genes at the molecular level, and (4) to identify additional components with kik-like phenotypes by mutagenesis screening. The characterization of Kik and Hippo action will provide a clearer picture of the regulatory network that controls cell proliferation. Because developmental mechanisms are generally highly conserved between Drosophila and vertebrates, our results will have implications for understanding normal human development and the causes of cancer.